S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis
Introduction and objectives Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously...
| Main Authors: | , , , , , |
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| Format: | Article |
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BMJ Publishing Group
2016
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| Online Access: | https://eprints.nottingham.ac.uk/47500/ |
| _version_ | 1848797561800884224 |
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| author | Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua |
| author_facet | Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua |
| author_sort | Brand, Oliver J. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Introduction and objectives Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously demonstrated distinct epigenetic modifications involved in repression of the antifibrotic gene cyclooxygenase-2 (COX-2) in fibroblasts from IPF (F-IPF) lungs compared with fibroblasts from non-fibrotic lungs (F-NL). Epigenetic drugs capable of inhibiting DNA and histone modifications may, therefore, represent a putative novel therapy. The aim of this study was to investigate the ability of 4 epigenetic inhibitors to regulate TGF-β-driven fibrosis in ex vivo mouse lung.
Methods A precision-cut lung slice (PCLS) model of fibrosis was established using the previously described1 CC10-tTS-rtTA-TGFβ1 transgenic (tgTGF-β1) mouse. The model was first assessed by investigating PCLS overexpression of TGF-β1 in response to stimulation of the transgene by doxycycline treatment. Gene expression of COX-2 and fibrotic markers including collagen were assessed after 4 days of treatment. The anti-fibrotic potential of 4 epigenetic inhibitors; BIX01294 (BIX, inhibitor of G9a histone methyltransferase), 3-deazaneplanocin A (DZNep, inhibitor of EZH2 histone methyltransferase), SAHA (inhibitor of histone deacetylases, HDACs) and Decitabine (DAC, DNA demethylating agent) was investigated. Viability of PCLS was assessed by MTT and Prestoblue® assay.
Results Treatment of PCLS from tgTGF-β1 mice with doxycycline induced a concentration-dependent increase in global TGF-β1, pro-fibrotic markers including collagen and pro-inflammatory COX-2, which was comparable to recombinant TGF-β1 treatment. Treatment with three of the epigenetic inhibitors BIX01294, DZNep and DAC did not reduce the pro-fibrotic response following doxycycline treatment. However SAHA demonstrated a significant suppressive effect on COX-2 and collagen expression, while not directly affecting TGF-β1 transgene expression.
Conclusions The data suggests that SAHA has the potential to reduce fibrosis in a TGF-β1 driven model of pulmonary fibrosis. Further work is currently underway to assess the anti-fibrotic potential of this drug in tgTGF-β1 animals. |
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| format | Article |
| id | nottingham-47500 |
| institution | University of Nottingham Malaysia Campus |
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| last_indexed | 2025-11-14T20:05:50Z |
| publishDate | 2016 |
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| spelling | nottingham-475002020-05-04T18:18:26Z https://eprints.nottingham.ac.uk/47500/ S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua Introduction and objectives Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously demonstrated distinct epigenetic modifications involved in repression of the antifibrotic gene cyclooxygenase-2 (COX-2) in fibroblasts from IPF (F-IPF) lungs compared with fibroblasts from non-fibrotic lungs (F-NL). Epigenetic drugs capable of inhibiting DNA and histone modifications may, therefore, represent a putative novel therapy. The aim of this study was to investigate the ability of 4 epigenetic inhibitors to regulate TGF-β-driven fibrosis in ex vivo mouse lung. Methods A precision-cut lung slice (PCLS) model of fibrosis was established using the previously described1 CC10-tTS-rtTA-TGFβ1 transgenic (tgTGF-β1) mouse. The model was first assessed by investigating PCLS overexpression of TGF-β1 in response to stimulation of the transgene by doxycycline treatment. Gene expression of COX-2 and fibrotic markers including collagen were assessed after 4 days of treatment. The anti-fibrotic potential of 4 epigenetic inhibitors; BIX01294 (BIX, inhibitor of G9a histone methyltransferase), 3-deazaneplanocin A (DZNep, inhibitor of EZH2 histone methyltransferase), SAHA (inhibitor of histone deacetylases, HDACs) and Decitabine (DAC, DNA demethylating agent) was investigated. Viability of PCLS was assessed by MTT and Prestoblue® assay. Results Treatment of PCLS from tgTGF-β1 mice with doxycycline induced a concentration-dependent increase in global TGF-β1, pro-fibrotic markers including collagen and pro-inflammatory COX-2, which was comparable to recombinant TGF-β1 treatment. Treatment with three of the epigenetic inhibitors BIX01294, DZNep and DAC did not reduce the pro-fibrotic response following doxycycline treatment. However SAHA demonstrated a significant suppressive effect on COX-2 and collagen expression, while not directly affecting TGF-β1 transgene expression. Conclusions The data suggests that SAHA has the potential to reduce fibrosis in a TGF-β1 driven model of pulmonary fibrosis. Further work is currently underway to assess the anti-fibrotic potential of this drug in tgTGF-β1 animals. BMJ Publishing Group 2016-12-01 Article PeerReviewed Brand, Oliver J., Pasini, Alice, Habgood, Antony, Knox, Alan J., Jenkins, Gisli and Pang, Linhua (2016) S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis. Thorax, 71 (Supp 3). A31. ISSN 1468-3296 http://thorax.bmj.com/content/71/Suppl_3/A31.2 doi:10.1136/thoraxjnl-2016-209333.58 doi:10.1136/thoraxjnl-2016-209333.58 |
| spellingShingle | Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title | S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_full | S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_fullStr | S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_full_unstemmed | S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_short | S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_sort | s52 suberanilohydroxamic acid (saha) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (pcls) model of pulmonary fibrosis |
| url | https://eprints.nottingham.ac.uk/47500/ https://eprints.nottingham.ac.uk/47500/ https://eprints.nottingham.ac.uk/47500/ |